title: NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders.
abstract: Gain-of-function mutations of Na(V)1.7 have been shown to produce two distinct disorders: Na(V)1.7 mutations that enhance activation produce inherited erythromelalgia (IEM), characterized by burning pain in the extremities; Na(V)1.7 mutations that impair inactivation produce a different, nonoverlapping syndrome, paroxysmal extreme pain disorder (PEPD), characterized by rectal, periocular, and perimandibular pain. Here we report a novel Na(V)1.7 mutation associated with a mixed clinical phenotype with characteristics of IEM and PEPD, with an alanine 1632 substitution by glutamate (A1632E) in domain IV S4-S5 linker. Patch-clamp analysis shows that A1632E produces changes in channel function seen in both IEM and PEPD mutations: A1632E hyperpolarizes (-7 mV) the voltage dependence of activation, slows deactivation, and enhances ramp responses, as observed in Na(V)1.7 mutations that produce IEM. A1632E depolarizes (+17mV) the voltage dependence of fast inactivation, slows fast inactivation, and prevents full inactivation, resulting in persistent inward currents similar to PEPD mutations. Using current clamp, we show that A1632E renders dorsal root ganglion (DRG) and trigeminal ganglion neurons hyperexcitable. These results demonstrate a Na(V)1.7 mutant with biophysical characteristics common to PEPD (impaired fast inactivation) and IEM (hyperpolarized activation, slow deactivation, and enhanced ramp currents) associated with a clinical phenotype with characteristics of both IEM and PEPD and show that this mutation renders DRG and trigeminal ganglion neurons hyperexcitable. These observations indicate that IEM and PEPD mutants are part of a physiological continuum that can produce a continuum of clinical phenotypes.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: M
authors.initials: M
authors.lastname: Estacion
authors.forename: S D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: P J
authors.initials: PJ
authors.lastname: Benke
authors.forename: Rene H M
authors.initials: RH
authors.lastname: Te Morsche
authors.forename: E M
authors.initials: EM
authors.lastname: Eastman
authors.forename: L J
authors.initials: LJ
authors.lastname: Macala
authors.forename: J P H
authors.initials: JP
authors.lastname: Drenth
authors.forename: S G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000409:Alanine / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002648:Child; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation; D004916:Erythromelalgia / Q000150:complications / Q000235:genetics*; D005727:Ganglia, Spinal / Q000166:cytology; D018698:Glutamic Acid / Q000235:genetics*; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D008958:Models, Molecular; D009154:Mutation; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000235:genetics*; D013001:Somatoform Disorders / Q000150:complications / Q000235:genetics*; D013997:Time Factors; D014162:Transfection
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels; D018698:Glutamic Acid; D000409:Alanine